Therapies against malignant pleural mesothelioma (MPM) have yielded disappointing results, in part, because pathologic mechanisms remain obscure. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in MPM. Cox proportional hazards regression analysis delineated associations between higher MTDHexpression and lower patient survival from three independent MPM cohorts (n = 349 patients). Through in vitroassays with overexpression and downregulation constructs in MPM cells, we characterized the role of MTDH. We confirmed in vivothe phenotype of altered MTDHexpression in a murine xenograft model. Transcriptional regulators of MTDHwere identified by chromatin immunoprecipitation. Overexpression of both MTDHmRNA (12-fold increased) and protein levels was observed in tumor tissues. MTDH stable overexpression significantly augmented proliferation, invasiveness, colony formation, chemoresistance, and an antiapoptosis phenotype, while its suppression showed opposite effects in MPM cells. Interestingly, NF-κBand c-Myc(in a feed-forward loop motif) contributed to modulating MTDHexpression. Knockdown of MTDHexpression profoundly retarded xenograft tumor growth. Thus, our findings support the notion that MTDHintegrates upstream signals from certain transcription factors and mediates pathogenic interactions contributing to MPM traits. MTDH represents a new MPM-associated gene that can contribute to insights of MPM biology and, as such, suggest other treatment strategies.